Combination therapies for the treatment of cancer

Abstract

The present disclosure provides methods of treating cancer with a combination therapies of a SHP2 inhibitor, such as the compound of Formula I, and an FGFR inhibitor, a B-Raf inhibitor, a MEK inhibitor, or a MET inhibitor

1 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with an FGFR inhibitor. 
       
     
     
         2 . The method of  claim 1 , wherein the FGFR in the subject is constitutively active. 
     
     
         3 . The method of  claim 1  or  2 , wherein the cancer lung cancer. 
     
     
         4 . The method of  claim 1  or  2 , wherein the cancer is hepatocellular carcinoma. 
     
     
         5 . The method of  claim 1  or  2 , wherein the cancer is cholangiocarcinoma. 
     
     
         6 . The method of  claim 1  or  2 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         7 . The method of any one of  claims 1  to  5 , wherein the inhibitor is selected from the group consisting of erdafitinib, AZD4547, Ly2874455, CH5183284, NVP-BGJ398, INCB054828, rogaratinib, PRN1371, TAS-120, BLU-554, H3B-6527, andFGF401. 
     
     
         8 . The method of any one of  claims 1  to  5 , wherein the FGFR inhibitor is erdafitinib. 
     
     
         9 . The method of any one of  claims 1  to  5 , wherein the FGFR inhibitor is pemigatinib, infigratinib, dovitinib, ponatinib, nintedanib, and fisogatinib. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein the method comprises administering a third MAPK pathway inhibitor. 
     
     
         11 . The method of any one of  claims 1  to  10 , wherein the administration is oral. 
     
     
         12 . The method of any one of  claims 1  to  11 , wherein the dosing of the compound of Formula I is in a range from 20 mg to 400 mg daily. 
     
     
         13 . The method of any one of  claims 1  to  12 , wherein the dosing of the FGFR inhibitor is in a range from 1 mg to 500 mg daily. 
     
     
         14 . A method of treating liver cancer in a subject comprising orally administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with erdafitinib. 
       
     
     
         15 . The method of  claim 14 , wherein the compound of Formula I is administered once or twice daily. 
     
     
         16 . The method of  claim 14  or  15 , wherein erdafitinib is administered once or twice daily. 
     
     
         17 . The method of  claim 14 , wherein the subject is a human. 
     
     
         18 . A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and an FGFR inhibitor. 
     
     
         19 . The kit of  claim 18 , wherein the compound of Formula I and the FGFR inhibitor are in separate packages. 
     
     
         20 . The kit of  claim 18  or  19 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of cancer. 
     
     
         21 . The kit of any of  claims 18  to  20 , wherein the FGFR inhibitor is one or more of erdafitinib, AZD4547, Ly2874455, CH5183284, NVP-BGJ398, INCB054828, rogaratinib, PRN1371, TAS-120, BLU-554, H3B-6527, FGF401, pemigatinib, infigratinib, dovitinib, ponatinib, nintedanib, and fisogatinib. 
     
     
         22 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with an inhibitor of a B-Raf protein having a class 1 mutation. 
       
     
     
         23 . The method of  claim 22 , wherein the class 1 mutation is V600E. 
     
     
         24 . The method of  claim 22  or  23 , wherein the cancer is colorectal cancer. 
     
     
         25 . The method of  claim 22  or  23 , wherein the cancer is melanoma. 
     
     
         26 . The method of  claim 22  or  23 , wherein the cancer is thyroid cancer. 
     
     
         27 . The method of  claim 22  or  23 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         28 . The method of any one of  claims 22  to  27 , wherein the inhibitor is selected from the group consisting of encorafenib, vemurafenib, dabrafenib, sorafenib, and regorafenib. 
     
     
         29 . The method of any one of  claims 22  to  27 , wherein the inhibitor is encorafenib. 
     
     
         30 . The method of any one of  claims 22  to  27 , wherein the inhibitor is vemurafenib. 
     
     
         31 . The method of any one of  claims 22  to  27 , wherein the inhibitor is dabrafenib. 
     
     
         32 . The method of any one of  claims 22  to  27 , wherein the inhibitor is sorafenib. 
     
     
         33 . The method of any one of  claims 22  to  27 , wherein the inhibitor is regorafenib. 
     
     
         34 . The method of any one of  claims 22  to  33 , wherein the method comprises administering a third MAPK pathway inhibitor. 
     
     
         35 . The method of any one of  claims 22  to  34 , wherein the administration is oral. 
     
     
         36 . The method of any one of  claims 22  to  35 , wherein the dosing of the compound of Formula I is in a range from 20 mg to 400 mg daily. 
     
     
         37 . The method of any one of  claims 22  to  36 , wherein the dosing of the B-Raf inhibitor is in a range from 1 mg to 500 mg. 
     
     
         38 . A method of treating colorectal cancer in a subject comprising orally administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with B-Raf inhibitor encorafenib. 
       
     
     
         39 . The method of  claim 38 , wherein the compound of Formula I is administered once or twice daily. 
     
     
         40 . The method of  claim 38  or  39 , wherein encorafenib is administered once or twice daily. 
     
     
         41 . The method of claim any one of  claims 38  to  40 , wherein the subject is human. 
     
     
         42 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with encorafenib. 
       
     
     
         43 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with vemurafenib 
       
     
     
         44 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with dabrafenib 
       
     
     
         45 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with sorafenib. 
       
     
     
         46 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with regorafenib. 
       
     
     
         47 . The method of any one of  claims 42  to  46 , wherein the cancer is colorectal cancer. 
     
     
         48 . The method of any one of  claims 42  to  46 , wherein the cancer is thyroid cancer. 
     
     
         49 . The method of any one of  claims 42  to  46 , wherein the cancer is melanoma. 
     
     
         50 . The method of any one of  claims 42  to  46 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         51 . The method of any one of  claims 22  to  50 , wherein a dosing of the B-Raf inhibitor is less than a dosing required for a monotherapy with the B-Raf inhibitor. 
     
     
         52 . The method of any one of  claims 22  to  51 , wherein a dosing of the compound of Formula I is less than a dosing required for a monotherapy with the compound of Formula I. 
     
     
         53 . A method of inhibiting ERK1/2 phosphorylation in a cell population comprising contacting a cell population with the compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with regorafenib. 
       
     
     
         54 . The method of  claim 53 , wherein a concentration of the compound of Formula I is a range from 1 nM to 500 nM. 
     
     
         55 . The method of  claim 53  or  54 , wherein a concentration of encorafenib is in a range from 10 nM to 20 nM. 
     
     
         56 . A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a B-Raf inhibitor. 
     
     
         57 . The kit of  claim 56 , wherein the compound of Formula I and the B-Raf inhibitors are in separate packages. 
     
     
         58 . The kid of  claim 56  or  57 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of cancer. 
     
     
         59 . The kit of any one of  claims 56  to  58 , wherein the B-Raf inhibitor is one or more of encorafenib, vemurafenib, dabrafenib, sorafenib, and regorafenib. 
     
     
         60 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with a MEK inhibitor. 
       
     
     
         61 . The method of  claim 60 , wherein the MEK inhibitor inhibits MEK1 selectively or MEK2 selectively or both MEK1 and MEK2 selectively. 
     
     
         62 . The method of  claim 60 , wherein the cancer is metastatic. 
     
     
         63 . The method of any one of  claims 60  to  62 , wherein the cancer colorectal cancer. 
     
     
         64 . The method of any one of  claims 60  to  62 , wherein the cancer is melanoma. 
     
     
         65 . The method of any one of  claims 60  to  62 , wherein the cancer is lung cancer. 
     
     
         66 . The method of any one of  claims 60  to  62 , wherein the cancer is pancreatic cancer. 
     
     
         67 . The method of any one of  claims 60  to  62 , wherein the cancer is breast cancer. 
     
     
         68 . The method of any one of  claims 60  to  62 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         69 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, binimetinib, PD-0325901, selumetinib and CI-1040. 
     
     
         70 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is trametinib. 
     
     
         71 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is cobimetinib. 
     
     
         72 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is binimetinib. 
     
     
         73 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is PD-325901. 
     
     
         74 . The method of any one of  claims 60  to  68 , wherein the MEK inhibitor is CI-1040. 
     
     
         75 . The method of any one of  claims 60  to  74 , wherein the method comprises administering a further MAPK pathway inhibitor. 
     
     
         76 . The method of any one of  claims 60  to  75 , wherein the administration is oral. 
     
     
         77 . The method of any one of  claims 60  to  76 , wherein the dosing of the compound of Formula I is in a range from 20 mg to 400 mg daily. 
     
     
         78 . The method of any one of  claims 60  to  77 , wherein the dosing of the MEK inhibitor is in a range from 1 mg to 500 mg daily. 
     
     
         79 . A method of treating cancer in a subject comprising orally administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with MEK inhibitor binimetinib or trametinib. 
       
     
     
         80 . The method of  claim 79 , wherein the compound of Formula I is administered once or twice daily. 
     
     
         81 . The method of  claim 79  or  80 , wherein binimetinib or trametinib is administered once or twice daily. 
     
     
         82 . The method of any one of  claims 79  to  81 , wherein the subject is a human. 
     
     
         83 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with binimetinib. 
       
     
     
         84 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with trametinib. 
       
     
     
         85 . The method of  claim 83  or  84 , wherein the cancer is colorectal cancer. 
     
     
         86 . The method of  claim 83  or  84 , wherein the cancer is lung cancer. 
     
     
         87 . The method of  claim 83  or  84 , wherein the cancer is melanoma. 
     
     
         88 . The method of  claim 83  or  84 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         89 . The method of any one of  claims 60  to  88 , wherein a dosing of the MEK inhibitor is less than a dosing required for a monotherapy with the MEK inhibitor. 
     
     
         90 . The method of any one of  claims 60  to  89 , wherein a dosing of the compound of Formula I is less than a dosing required for a monotherapy with the compound of Formula I. 
     
     
         91 . A method of inhibiting ERK1/2 phosphorylation comprising contacting a cell population with Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with binimetinib or trametinib. 
       
     
     
         92 . The method of  claim 91 , wherein a concentration of the compound of Formula I is in a range from 1 nM to 1,000 nM. 
     
     
         93 . The method of  claim 91  or  92 , wherein a concentration of MEK inhibitors is in a range from 10 nM to 500 nM. 
     
     
         94 . A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and an MEK inhibitor. 
     
     
         95 . The kit of  claim 94 , wherein the compound of Formula I and the MEK inhibitor are in separate packages. 
     
     
         96 . The kit of  claim 94  or  95 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of cancer. 
     
     
         97 . The kit of any of  claims 94  to  96 , wherein the MEK inhibitor is one or more of trametinib or binimetinib. 
     
     
         98 . A method of treating a subject having cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with a MET inhibitor. 
       
     
     
         99 . The method of  claim 98 , wherein the MET inhibitor is also an ALK inhibitor, a ROS1 inhibitor, or both. 
     
     
         100 . The method of  claim 98  or  99 , wherein the cancer is non-small lung cancer. 
     
     
         101 . The method of  claim 98  or  99 , wherein the cancer is stomach cancer. 
     
     
         102 . The method of  claim 98  or  99 , wherein the cancer is gastric adenocarcinoma. 
     
     
         103 . The method of  claim 98  or  99 , wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). 
     
     
         104 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is selected from the group consisting of crizotinib, tepotinib, savolitinib, cabozantinib, and tivantinib. 
     
     
         105 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is crizotinib. 
     
     
         106 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is tepotinib. 
     
     
         107 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is savolitinib. 
     
     
         108 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is cabozantinib. 
     
     
         109 . The method of any one of  claims 98  to  103 , wherein the MET inhibitor is tivantinib. 
     
     
         110 . The method of any one of  claims 98  to  109 , wherein the method comprises administering a third MAPK pathway inhibitor. 
     
     
         111 . The method of any one of  claims 98  to  110 , wherein the administration is oral. 
     
     
         112 . The method of any one of  claims 98  to  111 , wherein the dosing of the compound of Formula I is in a range from 10 mg to 500 mg daily. 
     
     
         113 . The method of any one of  claims 98  to  112 , wherein the dosing of the inhibitor is in a range from 20 mg to 400 mg daily. 
     
     
         114 . A method of treating stomach cancer in a subject comprising orally administering to the subject a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         in combination with crizotinib. 
       
     
     
         115 . The method of  claim 114 , wherein the compound of Formula I is administered once or twice daily. 
     
     
         116 . The method of  claim 114  or  115 , wherein crizotinib is administered once or twice daily. 
     
     
         117 . The method of any one of  claims 114  to  116 , wherein the subject is a human. 
     
     
         118 . A kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a MET inhibitor. 
     
     
         119 . The kit of  claim 118 , wherein the compound of Formula I and the MET inhibitor are in separate packages. 
     
     
         120 . The kit of  claim 118  or  119 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of cancer. 
     
     
         121 . The kit of any of  claims 118  to  120 , wherein the MET inhibitor is one or more of crizotinib, tepotinib, savolitinib, cabozantinib, and tivantinib. 
     
     
         122 . The method of any one of  claims 1  to  121 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition. 
     
     
         123 . The method of any one of  claims 1  to  122 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is formulated as an oral composition. 
     
     
         124 . The method of any one of  claims 1  to  123 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once or twice a day. 
     
     
         125 . The method of any one of  claims 1  to  124 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered over a continuous 28-day cycle. 
     
     
         126 . The method of any one of  claims 1  to  125 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day in the amount of about 10 mg to about 140 mg. 
     
     
         127 . The method of any one of  claims 1  to  126 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day for a 3-week cycle, comprising 2 weeks of administration of the compound followed by 1 week of no administration of the compound. 
     
     
         128 . The method of any one of  claims 1  to  126 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day for a 4-week cycle, comprising 3 weeks of administration of the compound followed by 1 week of no administration of the compound. 
     
     
         129 . The method of any one of  claims 1  to  128 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered over a period of 6 weeks. 
     
     
         130 . The method of any one of  claims 1  to  128 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered over a period of 8 weeks. 
     
     
         131 . The method of any one of  claims 1  to  130 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered 3 times a week. 
     
     
         132 . The method of  claim 131 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 3, and day 5 of the week. 
     
     
         133 . The method of any one of  claims 1  to  132 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered 4 times a week. 
     
     
         134 . The method of  claim 133 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered for a 3-week cycle, comprising 2 weeks of administration of the compound followed by 1 week of no administration of the compound. 
     
     
         135 . The method of  claim 133 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered for a 4-week cycle, comprising 3 weeks of administration of the compound followed by 1 week of no administration of the compound. 
     
     
         136 . The method of any one of  claims 1  to  125 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered twice a day, two days per week. 
     
     
         137 . The method of any one of  claims 1  to  126 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered over a period of 8 weeks. 
     
     
         138 . The method of  claim 136  or  137 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered on day 1 and day 2 of each week. 
     
     
         139 . The method of any one of  claims 1  to  138 , wherein the cancer is selected from lung cancer, stomach cancer, liver cancer, colon cancer, kidney cancer, breast cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), juvenile myelomonocytic leukemia, neurolastoma, melanoma, and acute myeloid leukemia.